Olivier Saulnier: Cellular origins of medulloblastoma

Olivier Saulnier, Junior Group Leader at Institut Curie, made the following post on X:

“Excited to share our new paper in Cell on the cellular origins of medulloblastoma. We identify a PRTG+ve stem cell population in the human first trimester as the putative initiator of Group 3 medulloblastoma.

Thanks to the fantastic pioneering work from Parthiv Haldipur and Dr. Kathleen Millen, we and others have showed that Group 3 and Group4 medulloblastoma arise from the human cerebellar rhombic-lip, which produces most of the neurons in the entire brain (https://doi.org/10.1038/s41586-022-05215-w).

Using scRNAseq, we showed that apical Gr3 cells resemble PRTG+ve stem cells in four-week-old human embryonic hindbrain. PRTG+ve cells are restricted to the ventricular zone of the rhombic lip (RL-VZ). PRTG is a cell surface marker known to repress neuronal differentiation.

To test the hypothesis that PRTG+ve RL-VZ stem cells constitute the right cell/lineage of origin for Gr3 MB, we transformed PRTG+ve cells from E9.5 mice. Transformed PRTG+ve cells were able to form tumors histologically similar to Gr3 MB with poor survival.

We demonstrated that PRTG+ve RL-VZ stem cells grow adjacent to an immature vascular plexus composed of CD34+ve endothelial cells. This architecture is maintained in Gr3 MB suggesting a symbiotic neurovascular niche.

Finally, we showed that targeting PRTG+ve cells in vivo (using diphtheria toxin, mAb or CAR-T) constitute an effective therapy for Gr3 medulloblastoma.

Overall, our model suggests that Gr3-MB is initiated during the first-to-second trimester of pregnancy, that Gr3 PRTG+ve stem cells form a symbiotic neurovascular niche to sustain an oncogenic ballet and our anti-PRTG CAR T cells represent an exciting therapeutic opportunity.

This was a huge team effort, and we thank our amazing co-authors! A big shout-out especially Abhi and Chuan! And a specific thanks to Michael Taylor and all the collaborators!!

Many thanks to The Hospital for Sick Children, Institut Curie, Baylor College of Medicine, University of Pittsburgh.”

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Source: Olivier Saulnier/X